intermediate 6 (419 mg, 2.2 mmol) in Et2O (16 mL) and dry
MeOH (0.1 mL) was treated with LiBH4 (97 mg, 4.4 mmol) at 0
°C and under nitrogen atmosphere. The reaction mixture was
allowed to attain to room temperature and stirred at that for 5 h.
The solution obtained was diluted with water (15 mL) and
extracted with Et2O (3 x 15 mL). The organic solution was
washed with H2O (15 mL), dried, filtered and the solvent was
concentrated in vacuo. The crude alcohol was purified by flash
chromatography (cyclohexane/EtOAc 70:30) and crystallized
from methanol. Spectral data are in agreement with data reported
for 2 h at room temperature. The reaction mixture was then
quenched with H2O (10 mL) and extracted with EtOAc (3 x 10
mL). The organic phases were dried with Na2SO4 and
concentrated in vacuo. The crude compound was purified by
flash chromatography (cyclohexane/EtOAc 40:60) and
crystallized by treatment with Et2O to give the desired final
products 10-11.
Spectral data of compounds 1-(4-benzylpiperidin-1-yl)-2-(5-
hydroxy-1H-indol-3-yl)ethanone (10) are in accordance with
1-[4-(4-Fluorobenzyl)piperidin-1-yl]-2-(5-hydroxy-1H-indol-
3-yl)ethanone (11):
4.1.3. Synthesis
yl)ethyl]-5-methoxy-1H-indole (8)
of
3-[2-(4-benzylpiperidin-1-
1
A solution of the alcohol 7 (516 mg, 2.7 mmol), and TEA (0.5
mL) in DCM (5 mL) was cooled to 0 °C, and methanesulfonyl
chloride (271 L, 3.5 mmol) dissolved in DCM (1 mL) was
added dropwise. After the mixture was stirred 45 min at room
temperature and then H2O (15 mL) and DCM (10 mL) were
added. The organic phase was separated, dried, and concentrated
in vacuo. The methanesulfonate ester (748 mg, 2.8 mmol)
obtained, was used without further purification. To a solution of
ester in acetone (10 mL), the 4-benzylpiperidine (492 L, 2.8
mmol) and K2CO3 (540 mg, 3.9 mmol) were added and the
solution was refluxed for 24h. Then, the solvent was evaporated,
and the residue was dissolved in H2O (15 mL) and Et2O (10 mL).
The organic phase was washed with H2O (3 x 5 mL), saturated
aqueous NaHCO3 (3 x 5 mL) and dried with Na2SO4. The final
Yield 96%; mp 190-191 C; Rf = 0.30 H NMR (DMSO-d6)
0.89-4.38 (m, 11H), 3.63 (s, 2H, CH2CO), 6.58 (d, 1H, ArH),6.88
(s, 1H, ArH), 7.07-7.18 (m, 6H, ArH), 8.57 (s, 1H, OH), 10.54
(bs, 1H, NH). Anal. Calcd for C22H23FN2O2: C, 72.11; H, 6.33;
N, 7.64. Found: C, 72.22; H, 6.23; N, 7.75.
The 2-chloro-1-(5-methoxy-1H-indol-3-yl)ethanone (13), and
2-chloro-1-(5-hydroxy-1H-indol-3-yl)ethanone
(14)
were
synthesized following a previously reported procedure and
spectral data are in accordance with literature. [14, 16]
4.1.6. General procedure for the synthesis of
compounds 15-19
To
a
solution of 2-chloro-1-(5-hydroxy-1H-indol-3-
yl)ethanone (1 mmol) (14) in DMF dry (5 mL) the proper
benzylpiperidines (1 mmol) or 4-phenoxypiperidine (1.5 mmol)
and K2CO3 (0.5 mmol) were added.
compound
3-[2-(4-benzylpiperidin-1-yl)ethyl]-5-methoxy-1H-
indole (8) was purified by flash chromatography (DCM/CH3OH
90:10) and crystallized from a mixture of Et2O and CH3OH.
The resulting mixture was subjected to microwave irradiation
(100 °C, 200 W) for 15 min and then was treated with a saturated
NaHCO3 (10 mL) aqueous solution and extracted with EtOAc (3
x 10 mL). The organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash
chromatography (DCM/CH3OH 90:10) and crystallized from
Et2O and EtOH to give the desired compounds.
1
Yield 40%; mp 110-112 °C; H NMR (CDCl3) 1.30-3.21
(m, 15H), 3.91 (s, 3H, OCH3), 6.90 (dd, 1H, J= 8.8, J= 2.4, ArH,
H-6), 7.00 (s, 1H, ArH), 7.12 (s, 1H, H-2), 7.20 (s, 1H, ArH),
7.22-7.39 (m, 5H, ArH), 8.61 (bs, 1H, NH). Anal.(C23H28N2O): C
79.27, H 8.10, N 8.04. Found: C 79.17, H 8.20, N 7.99.
4.1.4. Synthesis
of
3-[2-(4-benzylpiperidin-1-
yl)ethyl]-5-hydroxy-1H-indole (9)
1-(5-Hydroxy-1H-indol-3-yl)-2-(4-phenoxypiperidin-1-
The 3-[2-(4-benzylpiperidin-1-yl)ethyl]-5-hydroxy-1H-indole
(9) was prepared following a synthetic procedure fully described
by us earlier [16]. In particular 3-[2-(4-benzylpiperidin-1-
yl)ethyl]-5-methoxy-1H-indole (348 mg, 1 mmol) was dissolved
in methylene chloride (DCM) (5 mL), treated with BBr3 (1 M in
DCM) (6 mmol, 6 mL) under nitrogen atmosphere and stirred
overnight. After completion of reaction, MeOH (7 mL) was
carefully added at 0C and the solvent removed under reduced
pressure. The residue was dissolved in EtOAc (10 mL) and
washed with H2O (3 x 10 mL). The organic layer was dried
(Na2SO4) and concentrated in vacuo. The desired compound was
obtained by crystallization with Et2O.
yl)ethanone (15)
1
Yield 30%; mp 199-200 °C; Rf = 0.44; H NMR (DMSO-d6)
1.61-2.81 (m, 9H), 3.54 (s, 2H, CH2N), 6.66 (dd, 1H, J= 8.8,
J= 2.4, ArH, H-6), 6.88-7.27 (m, 6H, ArH),7.58 (d, 1H, J= 2.3,
ArH, H-4), 8.37 (s, 1H, H-2), 8.95 (bs, 1H, OH), 11.63 (bs, 1H,
NH). Anal.(C21H22N2O3): C 71.98, H 6.33, N 7.99. Found: C
71.86, H 6.44, N 7.89.
1-(5-Hydroxy-1H-indol-3-yl)-2-(4-(4-methylbenzyl)piperidin-
1-yl)ethanone (16)
1
Yield 30%; mp 215-216 °C; Rf = 0.23; H NMR (DMSO-d6)
1.09-2.90 (m, 11H), 2.25 (s, 3H, CH3), 3.47 (s, 2H, CH2N),
6.69 (dd, 1H, J= 8.5, J= 2.1, ArH, H-6), 7.02-7.06 (m, 4H, ArH),
7.24 (d, 1H, J= 8.5, ArH, H-7), 7.57 (d, 1H, J= 2.1, ArH, H-4),
8.35 (d, 1H, J= 3.2, H-2), 8.98 (s, 1H, OH), 11.63 (bs, 1H, NH).
Anal.(C23H26N2O2): C 76.21, H 7.23, N 7.73. Found: C 76.31, H
7.33, N 7.63.
1
Yield 40%; mp 205-207 °C; Rf = 0.17; H NMR (DMSO-d6)
1.06-2.77 (m, 15H), 6.53-6.58 (m, 2H, ArH), 6.66 (s, 1H,
ArH), 7.12 (s, 1H, H-2), 7.14-7.28 (m, 5H, ArH), 8.91 (bs, 1H,
OH), 9.99 (bs, 1H, NH). Anal.(C22H26N2O): C 79.01, H 7.84, N
8.38. Found: C 79.17, H 7.90, N 8.48.
4.1.5. General procedure for the synthesis of
derivatives 1-[4-(4-fluorobenzyl)piperidin-1-yl]-2-
(1H-indol-3-yl)ethanones (10-11)
2-(4-(4-Ethylbenzyl)piperidin-1-yl)-1-(5-hydroxy-1H-indol-3-
yl)ethanone (17)
1
Yield 50%; mp 199-200 °C; Rf = 0.28; H NMR (DMSO-d6)
A mixture of (5-hydroxy-1H-indol-3-yl)acetic acid (5) (0.5
1.06-2.90 (m, 16H), 3.47 (s, 2H, CH2N), 6.67 (dd, 1H, J= 8.8,
J= 3.0, ArH, H-6), 7.03-7.11 (m, 4H, ArH), 7.24 (d, 1H, J= 8.8,
ArH, H-7), 7.56 (d, 1H, J= 3.0, ArH, H-4), 8.34 (d, 1H, J= 2.9,
H-2), 8.96 (s, 1H, OH), 11.62 (bs, 1H, NH). Anal.(C24H28N2O2):
C 76.56, H 7.50, N 7.44. Found: C 76.46, H 7.55, N 7.53.
mmol)
with
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-
yl)uronium hexafluorophosphate (HBTU) (190 mg, 0.5 mmol) in
DMF (2 mL) was stirred for 30 min at room temperature.
Successively, the appropriate benzylpiperidine (1 mmol) and
TEA (70 L, 0.5 mmol) were added and the mixture was stirred